Methods and systems for improved bioavailability of active pharmaceutical ingredients including esomeprazole

ABSTRACT

The present disclosure relates to delivery systems and methods for increasing the bioavailability and increasing the absorption rate by monolithic enteric capsule administration to humans of active ingredients compared to the bioavailability of active ingredients enterically coated for modified release or gastric protection, particularly acid sensitive active ingredients such as esomeprazole, omeprazole, and other proton pump inhibitors, systems for delivering active pharmaceutical ingredients to humans or animals via monolithic enteric capsules, and improved methods of treating gastrointestinal disorders with such methods and delivery systems.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/899,586, filed Nov. 4, 2013, which is incorporated herein byreference in its entirety.

FIELD

The present disclosure relates to delivery systems and methods forincreasing the bioavailability of active ingredients by oral monolithicenteric capsule administration to humans, particularly theadministration of acid sensitive active ingredients such as omeprazole,esomeprazole, and other proton pump inhibitors, methods to deliveractive pharmaceutical ingredients to humans or animals via hardcapsules, and improved methods of treating gastrointestinal disorderswith such methods and delivery systems.

BACKGROUND

Modification of drug absorption has important implications for efficacy,tolerability, compliance and toxicity. Variable and delayed release drugdelivery systems have been pursued for mimicking biological processes aswell as for defining administration timing and location parameters. Manycomplicated systems have been proposed and some have been executed inthe modified release field; however, rapid drug release after a definedlag time remains a “major challenge.” Pragna, Pulsatile Drug DeliverySystem: An Overview, Int. J. Pharmaceutical Dev. & Technol., 3(2):97-105 (2013). Such lag time/pulsatile release delivery systems includevarious types and combinations of osmotic pumps, multiple coatings,plugs, orifices, tablets, and barriers. All of these prior systemsrequire significant development time and formulation expertise.

Multiparticulate dosage forms, with multiple release sites for activepharmaceutical ingredients, are expected to provide faster release rateprofiles in blood than monolithic dosage forms such as capsules.Residence time in the stomach strongly depends on the composition of thedosage form and the presence of food components, and multiparticulatedosage forms are expected to be emptied from the stomach quickly, on asimilar time scale as solutions, i.e., within 10 to 60 minutes in afasted state, or within 1-2 hours under a fed state. Gastric emptying ofa monolithic solid dosage form is delayed under a fed state, with arange of 4-7 hours depending on the caloric content of the meal. Gastricemptying time is shorter for multiparticulate dosage forms than formonolithic solid dosage forms, leading to correspondingly delayed pKvalues in blood for a monolithic dosage form.

Capsules are monolithic dosage forms widely used in the pharmaceuticalfield for oral administration to humans and animals of, e.g., variousactive ingredients, including pharmaceuticals, veterinary products, andfood and dietary supplements. Advantages of capsules over otherconventional dosage forms (such as tablets or liquids) may includebetter patient compliance, greater flexibility in dosage form design,taste masking, and less expensive manufacturing processes.

Capsules normally consist of a shell filled with one or more specificsubstances. The shell itself may be a soft or a hard capsule shell. Hardcapsule shells are generally manufactured using dip molding processes,which can be distinguished into two alternative procedures. In the firstprocedure, capsules are prepared by dipping stainless-steel mold pinsinto a solution of polymer, optionally containing one or more gellingagents (e.g. carrageenans) and co-gelling agents (e.g. inorganiccations). The mold pins are subsequently removed, inverted, and dried toform a film on the surface. The dried capsule films are then removedfrom the molds, cut to the desired length, and then the telescoping fitcaps and bodies are assembled together, printed, and packaged. See,e.g., U.S. Pat. Nos. 5,264,223, 5,756,123, and 5,756,123. In the secondprocedure, no gelling agents or co-gelling agents are used andfilm-forming polymer solution gelification on the molding pins isthermally induced by dipping pre-heated molding pins into the polymersolution. This second process is commonly referred to asthermogellation, or thermogelling dip molding. See, e.g., EP 0401832,U.S. Pat. Nos. 3,493,407, 4,001,211, and 3,617,588, GB 1310697, and WO2008/050209. The aforementioned manufacturing processes involve the useof solutions of the different ingredients that are needed for the makingthe telescoping fit hard capsule shells.

Hard capsules may be filled with active ingredients via procedures knownin the art. Typically, active ingredients are combined with variouscompatible excipients for ease of fill. The resulting fill may be a drypowder, a granulation, pellets, lipid pellets, a suspension, or aliquid. Additionally, stable, filled hard capsules have advantages overother dosage delivery forms such as liquids and solid tablets. Certainactive ingredients may be difficult to formulate into dry granules, ormay be otherwise incompatible with the tableting process. Anotherconsideration is improved patient compliance for taste-masking and easeof swallowing, i.e., capsules being preferred by consumers over tablets.

Acid labile or acid sensitive active ingredients, active ingredientsassociated with gastric damage or upset, or active ingredients whichdegrade in the stomach, may require particular formulation steps toprevent active ingredient degradation and/or irritation of the stomachmucosa. Such formulation steps include enteric coating, either ofmultiparticulates or granules, or of tablets formed from directcompaction and/or granulation of the active ingredients. Additionalprocessing steps (such as granulation, coating, and/or tableting) addmanufacturing complexity and resultant cost to pharmaceutical dosageforms. Other disadvantages include undesirable interaction with theenteric coating itself. For example, methacrylic acid copolymer, acommon enteric coating, has multiple acid groups, and thus must beseparated from acid sensitive active ingredients, for example, bypre-coating or protective coating in addition to an enteric coatinglayer, increasing the time, cost and complexity of the resulting dosageforms, whether granules, pellets, or tablets.

Another method for protecting acid sensitive active ingredients fromdegradation is the addition of a pH neutralizing agent, such as highlevels of sodium bicarbonate, see, e.g., ZEGERID® (omeprazole productfrom Santarus). While such a formulation avoids the need for a coatingstep, these buffer-containing dosage forms have a high sodium content(inadvisable for patients on sodium restricted diets) and the need for alarge amount of neutralizing agent results in a high formulation weightrequiring a large capsule size, at least capsule size #0.

While hard capsules may be coated in order to change the releasecharacteristics of the capsule, such coatings require additionalprocessing steps and are only able to be completed after activeingredient filling of a hard capsule. In addition, the amount and thecharacter of the coating must be adjusted by the end user for eachformulation so that the desired characteristics are obtained.

Proton pump inhibitors are acid labile and may be the cause of gastricdiscomfort, and include compounds such as dexlanzoprazole, esomeprazole,ilaprazole, leminoprazole, lanzoprazole, omeprazole, pantoprazole,paripiprazole, rabeprazole, tenatoprazole and pharmaceuticallyacceptable salts, derivatives and enantiomers thereof are known. Protonpump inhibitors are prescribed for the treatment of gastric-acid relateddiseases such as reflux esophagitis, gastric and duodenal ulcers,Zollinger-Ellison syndrome, and treatment of H. pylori infections.Various proton pump inhibitor compounds are known and sold commercially.The use of such compounds in enteric coated pellet form has beendisclosed, for example in U.S. Pat. No. 5,877,192 incorporated in itsentirety herein.

Esomeprazole (also known as perprazole, omeprazole S-form, and(−)-omeprazole) compositions are also commercially available, forexample, sold under the trademark NEXIUM® (Astra Zeneca) in 20 mg and 40mg doses, in tablet and capsule forms. Esomeprazole (as the magnesiumtrihydrate, C₃₄H₃₆MgN₆O₆S₂.3H₂O) has a molecular weight of 767.17 g/moland is slightly soluble in water (1.5 mg/ml in water at 25° C.), solublein methane and insoluble in heptane. Esomeprazole degrades in acidconditions but is stable at pH 6.8. Typical pharmaceutically effectiveamounts of esomeprazole for administration to humans range from about 5mg to about 80 mg, administered once or twice daily.

U.S. Pat. No. 5,714,504 to Lindberg describes optically pure salts ofomeprazole and methods for their use.

U.S. Patent Publication No. 2006/0280795 to Penhasi describes a deliverydevice for the delayed release of an active agent in thegastrointestinal tract with multiple coating and polymer layers.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean plasma concentrations for 14 patients versus timefor the monolithic esomeprazole enteric capsules without enteric coating(fed and fasted) according to Examples 6 and 7 and for the commercialdelayed release capsule product with enteric coated pellets.

FIG. 2 is a stick plot comparing the C_(max) (fasted) for the monolithicesomeprazole enteric capsule without enteric coating to the commercialdelayed release capsule product with enteric coated pellets for eachpatient.

FIG. 3 is a graphical analysis illustrating the median values in minutesfor the monolithic esomeprazole enteric capsules according to Examples 6and 7 compared to the commercial delayed release capsule product withenteric coated pellets.

DETAILED DESCRIPTION

The system and methods of the instant disclosure provide a fasterabsorption rate and shorter absorption times than the multiparticulateenteric coated dosage form. In one aspect, the enteric drug deliverysystem described herein comprises a monolithic enteric capsule filledwith at least one active pharmaceutical ingredient (API), wherein theAPI is without enteric coating for modified release or gastricprotection, and wherein said delivery system provides a short intestinalrelease time period and faster absorption rate following a lag time forrelease of said API upon administration to a human.

In another aspect, the present disclosure provides a method ofincreasing bioavailability of an active pharmaceutical ingredient (API),comprising administration to a human in need thereof a therapeuticallyeffective amount of at least one API in a monolithic enteric capsule,wherein said API is without enteric coating and wherein said deliverysystem provides a short intestinal release time period and a fasterabsorption rate following a lag time for release of said API, andwherein the bioavailability of said API is increased compared to APIdosage forms with enteric-coated granules (pellets) of esomeprazole.

Certain embodiments comprise a system for the delivery of at least oneacid labile active pharmaceutical ingredient by administering to afasting subject an oral dosage form comprising a monolithic entericcapsule filled with the active pharmaceutical ingredient, wherein theactive pharmaceutical ingredient has not been enterically coated formodified release or gastric protection, wherein less than about 10% ofthe active pharmaceutical ingredient is released from the monolithicenteric capsule after about 2 hours in a pH of about 1.2, wherein atleast about 80% of the active pharmaceutical ingredient is released fromthe monolithic enteric capsule after about 30 min at pH of about 6.8,and wherein more than about 95% of the active ingredient is released inthe intestine.

Certain embodiments comprise a system for the delivery of at least oneactive pharmaceutical ingredient that causes gastric side effects in afasting subject by administering to said subject an oral dosage formcomprising a monolithic enteric capsule filled with the activepharmaceutical ingredient, wherein the active pharmaceutical ingredienthas not been enterically coated for modified release or gastricprotection, wherein less than about 10% of the active pharmaceuticalingredient is released from the monolithic enteric capsule after about 2hours in a pH of about 1.2, wherein at least about 80% of the activepharmaceutical ingredient is released from the monolithic entericcapsule after about 30 min at pH of about 6.8, and wherein more thanabout 95% of the active ingredient is released in the intestine so thatgastric side effects are reduced or eliminated.

In certain embodiments, the present disclosure is also directed to asystem wherein the monolithic enteric capsule yields a peak plasmaconcentration (C_(max)) is equal to or higher than the peak plasmaconcentration achieved by the active pharmaceutical ingredient fromadministration of an oral dosage form comprising at least one entericcoating for modified release or gastric protection, particularly whereC_(max) is increased by up to about 279%.

In certain embodiments, the monolithic enteric capsule yields an AreaUnder Curve (AUC_(0-t)) plasma concentration of the activepharmaceutical ingredient equal to or higher than the AUC_(0-t) achievedby the active pharmaceutical ingredient from administration of an oraldosage form comprising at least one enteric coating for modified releaseor gastric protection, particularly where AUC_(0-t) is increased up toabout 220%.

The system according to any of the preceding claims, wherein themonolithic enteric capsule yields an Area Under Curve (AUC_(0-∞)) plasmaconcentration of the active pharmaceutical ingredient equal to or higherthan the AUC_(0-∞) achieved by the active pharmaceutical ingredient fromadministration of an oral dosage form comprising at least one entericcoating for modified release or gastric protection, particularly whereAUC_(0-∞) is increased up to about 162%.

In certain embodiments, the monolithic enteric capsule has an increasein oral bioavailability from about 10% to about 50% on average comparedto bioavailability of the active pharmaceutical ingredient in an oraldosage form comprising at least one enteric coating for modified releaseor gastric protection.

In certain embodiments, the active pharmaceutical ingredient is a protonpump inhibitor. In certain embodiments, the active pharmaceuticalingredient is selected from the group consisting of dexlanzoprazole,esomeprazole, ilaprazole, leminoprazole, lanzoprazole, omeprazole,pantoprazole, paripiprazole, rabeprazole, tenatoprazole andcombinations, pharmaceutically acceptable salts, derivatives, andenantiomers thereof. In certain embodiments, the active pharmaceuticalingredient is esomeprazole or its salt.

Certain embodiments comprise methods of increasing the bioavailabilityof an active pharmaceutical ingredient (API), comprising administrationto a human in need thereof a therapeutically effective amount of atleast one API in a monolithic enteric capsule, wherein said API has notbeen coated for modified release or gastric protection, wherein thebioavailability of said API is increased compared to API having anenteric coating for modified release or gastric protection. In certainembodiments, the API having an enteric coating comprises at least one ofbeads, pellets, granules, and spheres coated with an enteric coating formodified release or gastric protection. In certain embodiments, the APIis acid labile. In certain embodiments the API has gastric side effects.

Certain embodiments comprise an oral pharmaceutical dosage formcomprising a monolithic enteric hard capsule filled with at least oneproton pump inhibitor, wherein the monolithic enteric hard capsuleyields a peak plasma concentration higher than the peak plasmaconcentration achieved by the proton pump inhibitor having an entericcoating for modified release or gastric protection. In certainembodiments, the proton pump inhibitor lacking an enteric coating formodified release or gastric protection comprises uncoated esomeprazoleselected from beads, pellets, granules, spheres, and combinationsthereof.

Certain embodiments comprise a monolithic enteric capsule made by dipmolding from an aqueous composition comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer dispersed in water, whereinthe polymer is present in an amount ranging from about 15% to about 25%by weight of the total weight of the aqueous composition; at least onedispersant in an amount ranging from about 0.5% to about 2% by weight ofthe total weight of said aqueous composition; at least one gelling agentpresent in an amount ranging from about 0.1% to about 5% by weight ofthe total weight of said aqueous composition; and water; and wherein thedispersed polymer is partially neutralized with at least one alkalinematerial.

Certain embodiments comprise a monolithic enteric capsule made with anon-salified functional polymer, said polymer being present in an amountranging from about 50% to about 75% by weight of the total weight of theempty capsule; at least one processing aid present in an amount rangingfrom about 10.5% to about 20% by weight of the total weight of the emptycapsule; and water present in an amount ranging from about 1% to about20% by weight over the total weight of the empty capsule.

Certain embodiments comprise a monolithic enteric capsule comprisingcellulose acetate phthalate (CAP), in an amount ranging from about 40%to about 70% by weight; and at least one processing aid selected frompolyoxyethylene-polyoxypropylene-polyoxyethylene tri-block polymers andmixtures thereof, and having an average molecular weight ranging fromabout 1000 to about 20000 and a polyoxyethylene ratio ranging from about10% to about 80%, in an amount ranging from about 15% to about 49% byweight.

In certain embodiments, the monolithic enteric capsule for use in any ofthe systems and/or methods of the present disclosure lacks internalexcipients. In certain embodiments, the monolithic enteric capsuleremains substantially intact in the stomach.

In certain embodiments, the dosage form has an oral bioavailability thatis about 10% to about 50% higher than the bioavailability ofesomeprazole pellets or tablets having an enteric coating for modifiedrelease or gastric protection.

Certain embodiments comprise a method for delivering esomeprazole to afasting patient in need thereof, comprising administering to saidpatient an oral pharmaceutical dosage form comprising a monolithicenteric hard capsule filled with esomeprazole, wherein said esomeprazolehas not been enterically coated for modified release or gastricprotection, wherein more than about 95% of the esomeprazole is releasedfrom the capsule in the intestine, and wherein the pharmacokineticprofile exhibits a C_(max) of from about 700 ng/mL to about 2000 ng/mL,and a mean area under the plasma concentration-time curve fromadministration to about 12 hours (AUC₀₋₁₂) from about 800 ng·h/mL toabout 5000 ng·h/mL.

Certain embodiment comprise a dosage form comprising esomeprazole,wherein said esomeprazole has not been enterically coated for modifiedrelease or gastric protection, wherein the dosage form exhibits apharmacokinetic profile in a fasting patient wherein more than about 95%of the esomeprazole is released from the capsule in the intestine, andwherein the pharmacokinetic profile exhibits a C_(max) of from about 700ng/mL to about 2000 ng/mL, and a mean area under the plasmaconcentration-time curve from administration to about 12 hours (AUC₀₋₁₂)from about 800 ng·h/mL to about 5000 ng·h/mL.

Certain embodiments are directed to methods of improving treatment of agastrointestinal disorder in a human or other animal in need thereof,comprising administration of a monolithic enteric dosage form accordingto any of the preceding claims.

In certain embodiments, the monolithic enteric capsule for use in any ofthe preceding claims, wherein the monolithic enteric capsule provides anincreased rate of absorption the active pharmaceutical ingredient afteradministration to a patient as compared to the rate of absorption of theactive pharmaceutical ingredient having an enteric coating for modifiedrelease or gastric protection.

In certain embodiments, the monolithic enteric capsule provides anincreased rate of absorption C_(max)/(T_(max)−T_(lag)) for the activepharmaceutical ingredient after administration to a patient as comparedto the rate of absorption of the active pharmaceutical ingredient havingan enteric coating for modified release or gastric protection from about30 ng/mL/hr to about 3400 ng/mL/hr.

In certain embodiments, the monolithic enteric capsule decreases thetime to achieve peak plasma concentration (T_(max)−T_(lag)) for theactive pharmaceutical ingredient compared to the active pharmaceuticalingredient coated for modified release or gastric protection in pelletsor tablets, preferably decreasing by from about 0.1 hour to about 2.0hours. In certain embodiments, the monolithic enteric capsule decreasesthe time to achieve peak plasma concentration for the activepharmaceutical ingredient compared to the active pharmaceuticalingredient coated for modified release or gastric protection in pelletsor tablets, preferably decreasing by from about 10 minutes to about 90minutes.

In certain embodiments, the monolithic enteric capsule provides anincreased lag time after administration to a patient for release of theactive pharmaceutical ingredient compared to the active pharmaceuticalingredient coated for modified release or gastric protection in pelletsor tablets, preferably where the increase in lag time is from about 0.1hour to about 4.3 hours.

In some embodiments according to the present disclosure, the treatmentof gastrointestinal disorders is improved. These improvements may arisefrom, for example, faster and more complete release of the activeingredient, more effective application of the active ingredient(s) tothe proper portion of the gastrointestinal tract, improved patientcompliance, and decreased side effects.

“Administering” refers to any method which delivers the dosage formsused in this disclosure to the subject in need thereof so as to beeffective in the treatment of the disorder desired to be treated orameliorated. Oral administration of the dosage forms and administrationvia the stomach to the intestine and/or colon are of particularinterest.

“Area Under Curve” or “AUC” refers to the area under theconcentration-versus-time curve obtained by plotting the serum or plasmaconcentration of an active ingredient along the ordinate (Y-axis)against time along the abscissa (X-axis) for a defined time period.Generally, the values for AUC represent a number of values taken fromall the subjects in a subject test population and are, therefore, meanvalues averaged over the entire test population. By measuring the AUCfor a population to which the test composition has been administered andcomparing it with the AUC for the same population to which the controlhas been administered, the test composition can be evaluated. AUC's areused in the pharmaceutical arts and have been described, for example, in“Pharmacokinetics Processes and Mathematics”, Peter E. Welling, ACSMonograph 185; 1986. Correspondingly, “AUC_(0-t)” is the area under theplasma concentration versus time curve from time 0 (administration) totime t, and “AUC_(0-∞)” is the area under the plasma concentrationversus time curve from administration to infinity. “C_(max)” representsthe maximum drug concentration in serum or plasma of the test subject.“T_(max)” is the time after administration of an active ingredient whenthe maximum plasma concentration is reached. “CV” is the coefficient ofvariability. “K_(el)” is the elimination rate constant. “t_(1/2)” is theelimination half-life.

“Active ingredients,” “active pharmaceutical ingredients,” “drugs,” and“API” are used interchangeably herein, and APIs suitable for the presentdisclosure include APIs with a delivery profile which requires, orbenefits from, a lag time followed by a short intestinal release timeperiod. Non-limiting examples of such APIs include drugs that aremetabolized to pharmacological active compounds, drugs which have longin vivo half-lives showing an inherently prolonged duration of action,drugs with very short in vivo half-lives which require a prohibitivelylarge amount of active ingredients in a single dosage form, drugs whichrequire large doses for therapeutic effect, drugs which are required invery low doses, and drugs used in chronotherapy, e.g., medications takenat night whose actions are required in the early morning hours, drugsfor local gastrointestinal effects, drugs with upper intestineabsorption windows, and drugs that undergo extensive first passmetabolism. Classes of active ingredients suitable for the presentdisclosure include but are not limited to antibiotics, anti-inflammatorydrugs, anti-hypertensives, anti-anginal drugs, anti-neoplastic drugs,peptides, proteins, anti-rejection drugs, corticosteroids,anti-arthritics, anti-asthmatics, anti-sense oligonucleotides, andcombinations thereof.

Other classes of active ingredients suitable for the present disclosureinclude but are not limited to combination therapies such as ATRIPLA®(BMS; efavirenz, emtricitabine, tenofovir disoproxil fumarate), TRUVADA®(tenofovir DF and emtriva); VYTORIN® (Merck, ezetimibe/simvastatincombination) and contraceptives such as YAZ® (Bayer, drospirenone andethinyl estradiol).

In certain embodiments, the active ingredient is actonel, amlodipine,5-amino-salicylic acid, amylin, anastrozole, anidulafungin,aripiprazole, Atosiban, Bacitracin, bivalirudin, bleomycin,bromophenaramine, budesonide, candesartan, capecitabine, caspofungin,Cialis (tadalafil), conotoxin, Colistin, Crestor, cyclosporin,daptamycin, desmopressin, diovan, donepezil HCl, doxorubicin,Enfuvirtide, epoetin, eptifibatide, erlotinib, escitalopram,fenofibrate, 5-fluorouracil, Glucagon-like peptide-1 (GLP-1) AGONIST(e.g., exenatide and liraglutide), glucagon, gonadoreline, gramidicin,GV1001, histatin, hydrocortisone, ibuprofen, icatibant, imatinibmesylate, insulin, interferons, isosorbides, lactoferrin, Lanreotide,lisdexamfetamine dimesylate, Lypressin, memantine HCl, mesalamine,metoprolol, methylphenidate, micafungin, Micardis (HCT and telmisartan),MPB8298, mycophenolate sodium, nemifitide nesiritide, nicotine,nifedipine, Octreotide, ofloxacin, olanzapine, olmesartan, omiganan,oxyprenolol, oxytocin, pexiganan, pioglitazone HCl, prednisone,prednisolone, pseudoephedrine, protirelin, risedronate sodium,rotigaptide, sermorelin, saloatonin, somatropin, stimuvax, tacrolimus,tamsulosin, taxotere, Terlipressin, theophylline, Thymalfasin,urotoilitin, and combinations thereof; preferably imatinib mesylate,mesalamine, mycophenate sodium, ibuprofen, insulin, desmopressin, orsomatropin, and pharmaceutically acceptable combinations, salts,derivatives or enantiomers thereof.

In one embodiment, the active ingredient is a proton pump inhibitor,including but not limited to dexlanzoprazole, esomeprazole, ilaprazole,lanzoprazole, leminoprazole, omeprazole, pantoprazole, paripiprazole,rabeprazole, tenatoprazole, and pharmaceutically acceptablecombinations, salts, derivatives or enantiomers thereof. In oneembodiment, the active ingredient is esomeprazole in pellet form,without enteric coating.

“Enteric coating” as used herein refers to the process and result ofcoating a dosage form for modified release or gastric protection, anddoes not include banding or sealing of a telescoping capsule so as toprevent separation of the two capsule halves. “Enteric” as used hereinincludes delivery to any area of the small intestine and/or the colon.“Uncoated” as used herein refers to the lack of enteric coating, i.e.,lacking a coating designed to provide modified release or gastricprotection.

“Gastric side effects” as used herein includes both stomach andesophageal effects, including irritation, erosion, inflammation,ulcerations, pain, reflux, and other undesirable effects.

Hard capsules for use in certain embodiments include any telescoping,two piece capsule with bulk enteric and/or delayed release propertiesand can include capsules with acid resistant properties. Such capsulesinclude but are not limited to capsules according to WO 2012/056321,PCT/EP2013/055302, PCT/EP2013/055298, hereby incorporated by referencein their entirety, and DRCAPS™ acid resistant capsules (Capsugel). Thecapsules according to certain embodiments of the present disclosure, aresufficiently stable for administration to humans and other animals, anddisplay good mechanical properties, i.e., no cracking, discoloring,sticking, and/or deformation.

As used in the present disclosure, “gastrointestinal disorder” relatesto any infection, disease or other disorder of the gastrointestinalsystem, such as the upper and/or lower gastrointestinal tract. Suchdisorders include one or more of the following conditions: diarrhea,heartburn, indigestion, upset stomach, abdominal pain and/or cramping,flatulence, nausea, abdominal distention, fever, constipation, blood,mucus and/or pus present in feces, vomiting, gastroenteritis, weightloss, anorexia, malaise, and any other related condition.

“Monolithic enteric dosage form” relates to enteric hard capsules,formed by molding, and filled with an API, to protect the API fromstomach acid and to provide release of the API in the intestine of amammal after administration. Monolithic enteric dosage forms or capsulesexhibit these characteristics in the absence of any enteric coating,either on the capsule shell or on the API formulation. Additionalcomponents or excipients may optionally be filled within the enterichard capsules, such as other active ingredients and/or other excipients,for example, diluents, fillers, glidants, lubricants, disintegrants, orany other pharmaceutically suitable formulation excipients. In certainembodiments, the API alone is filled into the monolithic entericcapsules.

Certain embodiments of the monolithic enteric capsules mayadvantageously be sealed, by application of a sealing solution to thehard capsules by hand, or by automatic or mechanical means such as LEMS®70 System liquid encapsulation microspray sealing, and CFS technology(CFS 1200 liquid capsule filling and sealing system and CFS 1500Ccontainment capsule filling and sealing system) available from Capsugel.See, e.g., U.S. Pat. No. 7,645,407; EP 2083787. The seals or bands ofmonolithic enteric capsules are not a coating or an enteric coating,because it is not applied to the entire capsule and it is not intendedto modify release or provide gastric protection.

The clinical advantages of a system according to the present disclosureinclude increased absorption and higher bioavailability than aconventional immediate release or sustained release API due to thesystem's ability to release the API in a burst manner, enhanced deliveryof poorly bioavailable drugs that would be destroyed in the highergastrointestinal tract environment (for example, peptide molecules),reduced dose requirements of API without decrease in therapeutic effect,reduced side effects, reduced drug interactions due to lower receptorconcentration of cytochrome P450 isoenzymes, reduced food effect(bioavailability changes of drug when given with food), improved patientcompliance, chronotherapy-programmed delayed release of a drug foroptimal treatment of disease, pulsatile release, which allows multipledosing in a single dosage form; and site-specific intestinal release forlocal treatment of diseases.

The technological advantages of a system according to the presentdisclosure include protection of the API until its arrival at theintestinal site of release; separation of the API release from releasevariability caused by changes in the pH of the gastrointestinal tract;and separation of drug release from variability caused by changes oflumen content viscosity, because the system is not dependent on theagitation rate of the GI tract. Other advantages are that the system isnot colon flora dependent and is not dependent on the nature of thedrug. The system offers many parameters for controlling the releaseprofile and the lag time. See, e.g., Pragna et al.

One major advantage is that a system according to the present disclosureis based on standard pharmaceutical hard capsule filling equipment anddoes not rely on post-filling processing or coating variability. Becausethe hard capsule itself (without any enteric coating) exhibits thedesired enteric properties, active ingredient release is not dependenton the weight ratio of, or interactions between, formulation excipientsand active ingredients. The monolithic enteric capsule may contain anysolid dosage form such as beads, caplets, capsules, granules,microparticles, multiparticulates, microspheres; powders, pellets, solidlipid pellets, tablets, and combinations thereof, so long as the soliddosage form fits inside the particular hard capsule monolithic entericcapsule.

The following examples are merely illustrative, and should not beconstrued as limiting the present disclosure

Example 1

Enteric capsules were manufactured according to established dip moldingprocedures according to WO 2012/056321, incorporated herein in itsentirety by reference. The finished capsules comprised approximately 65%cellulose acetate phthalate (CAP), 20% poloxamer 188, 9% hydroxypropylmethyl cellulose acetyl succinate (HPMC-AS LF), with less thanapproximately 5% other excipients (including opacifier). After fillingwith active ingredients the monolithic enteric capsules were banded witha water/ethanol CAP solution using standard techniques.

Example 2

Esomeprazole was filled into capsules as pure esomeprazole magnesiumtrihydrate powder for comparative dissolution testing (pure EMT).

Esomeprazole was formulated as a powder blend by mixing 7.43% (w/w),22.3 mg/capsule of esomeprazole magnesium trihydrate powder withmicrocrystalline cellulose (grade Vivapur® 302, JRS Pharma) (91.57%%(w/w), 274.1 mg/capsule) with a 3-dimensional blender for 30 minutes at60 rpm. Magnesium stearate (1% (w/w), 3 mg/capsule) was added with 10minutes of additional mixing at 60 rpm. The resulting powder blend EMTwas filled into capsules (powder blend EMT).

Esomeprazole was formulated as EMT uncoated pellets by preparing anaqueous coating solution and coating onto sugar spheres (lacking entericcoating). The aqueous solution was formed by adding polysorbate 80(Tween® 80, Croda) to water (approximately 5 times the weight ofhydroxypropyl methyl cellulose, HPMC) under gentle stirring (330 rpm)until complete dissolution. The resulting solution was then heated at80° C. HPMC powder (HPMC 2010, PHARMACOAT® 606, Shin-Etsu) was thenadded in several steps, under stirring at 330 rpm, to promote thedispersion of the particles, as HPMC is insoluble in hot water. Heatingwas stopped once a homogeneous dispersion was achieved. The remainingcold water volume was then abruptly added, and the resulting solutionallowed to cool down at ambient temperature under stirring (stirringspeed adjusted to prevent bubble formation).

The EMT aqueous suspension of HPMC/polysorbate 80/EMT/water was preparedin a ratio of approximately 10.5/1/44.5/160. EMT powder blend was addedin several steps to the HPMC/polysorbate 80/water solution undervigorous stirring (1200 rpm).

The EMT aqueous suspension was coated onto inert beads (sugar spheres,grade 850-1000 micrometers, JRS Pharma). Inert beads were pre-heated for10 minutes (inlet air=53° C.) in a fluid-bed coater (GPCG-1, Glatt)equipped with a Wurster bottom-spray system. The aqueous EMT suspensionwas then sprayed onto the inert beads (atomizing pressure 1.5 bar) andthe layered beads were then subjected to a heating phase (10 min/53° C.)and finally dried under air flow (same flow rate, but without heating)until 30° C. was reached (EMT uncoated pellets).

The weight gain of the resulting EMT uncoated pellets at 20 mgesomeprazole dose was approximately 39.1%, with a 130-140 micrometerthickness of EMT coating after drying and a size D₁₀=1100.3μm/D₅₀=1154.0 μm/D₉₀=1219.2 μm. The final composition of the uncoatedpellets for a 20 mg esomeprazole dose per capsules is EMT 21.56% (w/w),22.3 mg; HPMC 5.09% (w/w), 5.25 mg; polysorbate 80 0.48% (w/w), 0.5 mg;and sugar spheres, 72.87% (w/w), 75.2 mg.

The 40 mg EMT uncoated pellet monolithic enteric capsules were filledwith 206.4 mg of uncoated pellets, and banded as described in Example 1.

Example 3 Dissolution Testing

Tested capsules prepared according to Examples 1-4 were filled with pureEMT, EMT uncoated pellets, or powder blend EMT equivalent to 20 mg ofesomeprazole. Commercial NEXIUM® (Astra Zeneca) products were purchasedin a drugstore and were tested as is (dosage=20 mg or 20 mgesomeprazole). The commercial product delayed release capsule is coatedpellets within a gelatin capsule, wherein the internal enteric coatedpellet formulation has glyceryl monostearate 40-55,hydroxypropylcellulose (HPC), hypromellose (HPMC), magnesium stearate,methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talcand triethyl citrate in a gelatin capsule (NEXIUM® patient leaflet,2012).

The commercial product is also available as a tablet (NEXIUM® tablets,“Multiple Unit Pellet System” or MUPS). The tablet's complex compositionincludes 17 excipients, starting from the same enteric coated pellets inthe delayed release capsule form plus microcrystalline cellulose, hardparaffin hard, Macrogol 6000, crospovidone, sodium stearyl fumarate, andcolorants (NEXIUM® tablets MUPS, patient leaflet, 2011).

The dissolution method was performed according to the USP monograph forEsomeprazole Magnesium Delayed-Release Capsule. Briefly, capsules weretested in apparatus 2 at 100 rpm, with sinker, at 37° C.±0.5° C.,wherein the acid stage is 2 hours in 300 mL of 0.1 N HCl medium,followed by the buffer stage which is the addition of 700 mL of 0.086Mdibasic sodium phosphate to adjust the pH to 6.8. The requirements underthe specifications are during the acid stage no unit more than 10%dissolved after 2 hours in 0.1N HCl medium, and buffer stage no unitless than 80% (Q+5%) dissolved after 30 min at pH 6.8. The measuredresults were the % EMT dissolved relative to the initial labelclaim/capsule dosage (20 mg).

For comparative purposes, the commercial esomeprazole delayed releasecapsule (20 mg) showed quick dissolution of the capsules but nodissolution of the pellets in the acid stage (EMT 120 minute mean was0%, n=6), and complete dissolution of the pellets during the bufferstage where the 30 minute mean for EMT release was 94% (n=6). Thecommercial enteric tablets product (20 mg) similarly showed nodissolution of the EMT from the tablets in the acid stage (EMT 120minute mean was 0%, n=6), and the 30 minute mean for EMT release fromthe tablets during the buffer stage was 94% (n=6).

The pure EMT in the monolithic enteric capsule showed no release of EMTin the acid stage and the capsule itself did not dissolve during theacid stage (three trials, 120 minute mean was 0%, n=6 each trial); thedissolution medium remained clear. The buffer stage gave completedisintegration of the capsules; the 30 minute mean for threemanufacturing trials provided 49% (n=6), 31% (n=6), and 65% (n=6) EMTrelease. Therefore, the monolithic enteric capsules showed good entericrelease even containing only pure powdered acid sensitive activeingredient, and without any need for enteric coating. This test wasdesigned to represent the theoretical maximum contact of acid sensitiveactive ingredient with the capsule shell.

Example 4

The EMT in the EMT powder blend prepared according to Example 2, filledinto the monolithic enteric capsule of Example 1, and tested accordingto the dissolution protocol of Example 3 showed no release of EMT in theacid stage and the capsule itself did not dissolve during the acid stage(two trials, 120 minute mean was 0%, n=6 each trial). The buffer stagegave complete disintegration of the capsules; the 30 minute mean for twomanufacturing trials provided 91% (n=6) and 93% (n=6) EMT release. Thepharmacopeia specifications for esomeprazole magnesium delayed releasecapsules were reached. Therefore, the monolithic enteric capsules showedexcellent enteric release containing a powdered blend of an acidsensitive active ingredient, and without any need for enteric coating.This dissolution result closely resembled the commercial tablet andcapsule product results.

Example 5

The EMT in the EMT uncoated pellets prepared according to Example 2,filled into the monolithic enteric capsules of Example 1, and testedaccording to the dissolution protocol of Example 3, showed no release ofEMT in the acid stage and the capsule itself did not dissolve during theacid stage (three trials, 120 minute mean was 0%, n=6 each trial), thedissolution medium remained clear. The buffer stage gave completedisintegration of the capsules after 20 minutes; the 30 minute mean forthree manufacturing trials provided 97% (n=6), 95% (n=6), and 98% (n=6)EMT release. The pharmacopeia specifications for esomeprazole magnesiumdelayed release capsules were reached. Therefore, the monolithic entericcapsules showed excellent enteric release containing uncoated pellets ofan acid sensitive active ingredient, and without any need for entericcoating. This dissolution result equaled or exceeded the commercialtablet and capsule product results.

Example 6 Pharmacoscintigraphy Testing

Monolithic enteric capsules were prepared according to Example 2, butsufficient uncoated pellets were added to provide a 40 mg esomeprazoledose. Radiolabelling was provided by adding approximately 4 MBq ^(99m)Tc(Technetium-99m, West of Scotland Radionuclide Dispensary, Glasgow) as aradioactive tracer, measured at the time of dosing. A suitable dose ofradioactivity (0.3 mSv in total) was chosen to provide a signal ofadequate quality while exposing the subjects to the minimum possibleradiation. Non-disintegrating pellets labeled with technetium-99mpertechnetate were added into each capsule (both the tested capsules andthe commercial product) to allow scintigraphic monitoring. Complexationof ^(99m)Tc to an anionic resin within the radiolabelled placebo pelletsprevented absorption of the radiopharmaceutical from the GI tract. Thetested capsules with ^(99m)Tc placebo pellets and EMT uncoated pelletsaccording to Example 6 were banded (see Example 1). The commercial 40 mgesomeprazole capsules (NEXIUM®)(“commercial product”) were opened andthe ^(99m)Tc placebo pellets were added; these immediate release gelatincapsules are not sealed at manufacture and so were not changed after theaddition of the radioactive tracer. The radiolabelled placebo pelletswere similar in size, shape, and density to the coated and uncoatedpellets containing the active ingredient.

Scintigraphy imaging via gamma camera was performed according tostandard medical diagnostic testing procedures with anterior andposterior images acquired at initial dosing and at regular timeintervals post initial dosing. Specifically, anterior and posteriorimages of 25 seconds each were acquired at dosing, then every 10 minutesto 2 hours post-dose, then every 15 minutes to 5 hours post-dose, thenevery 30 min to 12 hours post-dose with the subjects (standing position,Siemens E-Cam gamma camera fitted with a low-energy high-resolutioncollimator). Pharmacokinetic information was obtained via blood samplingpre-dose and at regular time intervals post initial dosing according toestablished procedures. The radiolabelled capsules (both Example 6 andcommercial capsules) were administered to the indicated number ofsubjects (Table 2). Subjects were dosed standing up and instructed toswallow the capsule whole with 240 mL room temperature water.

Table 1 illustrates the comparative location of release in vivo asdetermined from the scintigraphic imaging, and confirms enteric releaseof the monolithic enteric capsules under a fasting state. All of theExample 6 capsules released in either the small intestine or theileocecal junction, and none released in the stomach. In contrast, allof the commercial capsule product tested in patients released in eitherthe esophagus or the stomach (as expected from use of immediate releasegelatin capsules). No capsules failed to release and/or remained in thestomach or small intestine after 12 hours for either tested formulation.

TABLE 1 Esomeprazole Commercial Example 6 Product Site of Release Onset(n = 12) (n = 14) Esophagus 0 2 Stomach 0 12 Small intestine 11 0Ileocecal junction 1 0

Table 2 shows the release time profiles for median values given inminutes for the site of release onset under a fasting state as measuredby scintigraphic imaging. The monolithic enteric capsules opened onlyafter gastric emptying, but the commercial product, with enteric coatedpellets in a gelatin capsule, were released prior to gastric emptying.

TABLE 2 Esomeprazole Commercial Example 6 Product Site of Release Onset(n = 12) (n = 14) Gastric emptying of capsule 55 30 Onset ofradiolabelled pellets 90 5 release Completion of radiolabelled 120 30pellets release From gastric emptying to onset +35 −25 of pelletsrelease From onset to completion of 30 25 pellets release

Example 7 Pharmacokinetic Testing

Monolithic enteric capsules containing EMT uncoated pellets (40 mg)prepared as described in Example 6 were selected for in vivo testing ina randomized, open label, three-treatment, three period, three sequence,crossover, single dose pharmacoscintigraphy study in healthy volunteersand compared to the commercial esomeprazole delayed release capsuleNEXIUM® product (Astra Zeneca), which has enterically coated pellets.Time points for plasma sampling were pre-dose and 0.5, 0.75, 1.25, 1.5,2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, and 12 hours post-dose.Patients were selected from volunteers aged 18 to 65 years, inclusive,with a Body Mass Index (BMI) between 18.0 and 29.9 kg/m3 inclusive andfree from any significant diseases including cardiac, renal andgastrointestinal disease. Selected patients were randomized to threetreatment arms and three treatment sequences-monolithic enteric capsulefasted state, monolithic enteric capsule fed state, and commercialproduct fasted state. The crossover design eliminated potentialtreatment effects on the outcome, as well as effectively allowing thesubject to serve as his own control. Each dosing occasion was separatedby a 7-14 day washout period. Fasting conditions represented anovernight fast of at least 10 hours and fed state was after a highcalorie, high fat breakfast 30 minutes prior to dosing.

The % EMT was quantified from human plasma according to methods based onthe FDA Bioanalytical Method Validation Guide for Industry and the EMAGuideline on bioanalytical method validation (York BioanalyticalSolutions). Briefly, plasma samples were submitted to supported liquidextraction and liquid chromatography with tandem mass spectrometricdetection (lower limit of quantification 5.00 ng/ml with a samplealiquot volume of 100 microliters). The analytes detected wereesomeprazole, 5-hydroxyomeprazole, and omeprazole sulphone and werevalidated against commercial samples and calibration standards. Resultsobtained with 5-hydroxyomeprazole and omeprazole sulphone were similarto esomeprazole (not shown). Calibration samples were obtainedcommercially as follows: esomeprazole (Sigma-Aldrich),5-hydroxyomeprazole, and omeprazole sulphone (Toronto Chemicals Inc.).Internal standards omeprazole d3, 5-hydroxyomeprazole d3 and omeprazolesulphone-d3 were also utilized (Toronto Chemicals Inc.). Plasma sampleswere stored at −20° C. Data was collected using Analyst software(Applied Biosystems-Sciex) in combination with Watson LIMS (ThermoFisher Scientific); peak area ratios were used to generate calibrationcurves using regression functions.

The in vivo pharmacokinetic results obtained (shown in Tables 3 and 4)illustrate that the monolithic enteric capsule product surprisinglyexhibited a statistically significant delay in onset time ofquantifiable plasma concentrations as compared to the multiparticulate,enteric coated commercial dosage form of an acid sensitive activeingredient. The monolithic uncoated pellet product prepared according toExample 6 had an average onset time of 108 minutes, considerably longerthan the 66 minutes for the commercial product (p=0.0426).

Surprisingly, the monolithic enteric capsule product reached the highestplasma level (C_(max)) more rapidly than the commercial esomeprazoleproduct, i.e., within an average of 36 minutes as compared to an averageof 63 minutes (p=0.0166). This delivery system provides a shortintestinal release time period.

TABLE 3 Comparisons of quantifiable plasma concentrations and intestinalrelease and absorption time (fasting) Onset time in blood T_(max)Difference Comm. Comm. (T_(max) − Onset) Ex. 6 product Ex. 6 productComm. Subj Hrs min Hrs min Hrs min hrs min Ex. 6 Product 1 0.75 45 0.7545 1.25 75 1.25 75 30 30 2 1.02 61.2 0.85 51 1.27 76.2 2.02 121.2 1570.2 3 1.52 91.2 1.68 100.8 2.53 151.8 2.27 136.2 60.6 35.4 4 1.55 931.02 61.2 2.03 121.8 2 120 28.8 58.8 5 1.52 91.2 0.65 39 2.02 121.2 1.5291.2 30 52.2 6 0.78 46.8 3.03 181.8 1.27 76.2 5.02 301.2 29.4 119.4 82.02 121.2 0.52 31.2 2.52 151.2 1.5 90 30 58.8 9 1.52 91.2 0.52 31.22.02 121.2 1.25 75 30 43.8 10 0.52 31.2 0.75 45 1.02 61.2 2.53 151.8 30106.8 11 3.97 238.2 0.8 48 5.58 334.8 1.02 61.2 96.6 13.2 12 2.52 151.21.02 61.2 2.52 151.2 2.02 121.2 0 60 15 2.53 151.8 1.02 61.2 3.03 181.81.52 91.2 30 30 16 1.53 91.8 1.53 91.8 2.02 121.2 2.52 151.2 29.4 59.417 3.53 211.8 1.23 73.8 4.53 271.8 3.53 211.8 60 138 mean 1.81* 108.3*1.10* 65.87* 2.40 144.04 2.14 128.4 35.7** 62.57** SD 1.02 61.2 0.6539.2 1.28 77.0 1.06 63.6 23.1 35.9 Median 1.525 91.5 0.935 56.1 2.025121.5 2.01 120.6 30 58.8 Note: Statistical significance between Example6 and esomeprazole commercial product *p = 0.0426 in Kruskal-WallisTest; **p = 0.0166 in Kruskal-Wallis Test

TABLE 4 Comparison of the rate of absorption: C_(max)/(T_(max) −T_(lag)) (fasting) Ex. 6 (Enteric capsule filled with Commercial Product(capsule filled with uncoated pellets) enteric coated pellets) T_(max) −C_(max)/(T_(max) − T_(max) − C_(max)/(T_(max) − T_(lag) T_(max) C_(max)T_(lag) T_(lag)) T_(lag) T_(max) C_(max) T_(lag) T_(lag)) Subj (hr) (hr)(ng/mL) (hr) (ng/mL/hr) (hr) (hr) (ng/mL) (hr) (ng/mL/hr) 1 0.52 1.251770.00 0.73 2424.66 0.52 1.25 1610.00 0.73 2205.48 2 0.77 1.27 1430.000.50 2860.00 0.53 2.02 786.00 1.49 527.52 3 1.25 2.53 2380.00 1.281859.38 1.23 2.27 2170.00 1.04 2086.54 4 1.25 2.03 1020.00 0.78 1307.690.73 2.00 457.00 1.27 359.84 5 1.25 2.02 1260.00 0.77 1636.36 0.00 1.52874.00 1.52 575.00 6 0.53 1.27 1980.00 0.74 2675.68 2.53 5.02 1030.002.49 413.65 8 1.52 2.52 1420.00 1.00 1420.00 0.00 1.50 979.00 1.50652.67 9 1.27 2.02 1280.00 0.75 1706.67 0.00 1.25 981.00 1.25 784.80 100.00 1.02 801.00 1.02 785.29 0.52 2.53 559.00 2.01 278.11 11 3.52 5.58129.00 2.06 62.62 0.52 1.02 1830.00 0.50 3660.00 12 2.03 2.52 1450.000.49 2959.18 0.75 2.02 439.00 1.27 345.6 15 2.03 3.03 1140.00 1.001140.00 0.77 1.52 847.00 0.75 1129.33 16 1.18 2.02 1860.00 0.84 2214.291.27 2.52 1240.00 1.25 992.00 17 3.02 4.53 1430.00 1.51 947.02 1.02 3.531340.00 2.51 533.86 Mean 1.44 2.40 1382.14 0.96 1714.20* 0.74 2.141081.57 1.40 1038.89* SD 0.96 1.28 545.31 0.42 847.17 0.66 1.06 511.470.60 968.59 Median 1.25 2.03 1425.00 0.81 1671.52 0.63 2.01 980 1.27613.84

Statistical significance was obtained between Example 6 and thecommercial esomeprazole product * with a p value=0.0191 according to theKruskal-Wallis test. T_(lag) is the time prior to the first measurable(non-zero) concentration. The results shown in Table 4 illustrate thefaster absorption rate of the uncoated pellets in the enteric capsulecompared to the enteric coated beads of the commercial product.

The formula C_(max)/(T_(max)−T_(lag)) is used to measure the rate ofabsorption (where T_(lag) equals the measured time prior to the firstnon-zero drug concentration). Delayed release products are characterizedby the fact the drug release is internally delayed. Because of thedesigned delay, T_(max) alone would have limited meaning as a rate ofabsorption characteristic, and T_(max)−T_(lag) would provide a moremeaningful metric. In contrast to T_(max), C_(max) may not be affectedby the delayed release.

Esomeprazole in uncoated pellets in a monolithic enteric capsuleprepared according to Example 6 showed a significant difference in vivobetween C_(max)/(T_(max)−T_(lag)) compared to the commercial product ofenteric coated pellets in a gelatin capsule (P value<0.05), based uponactual hours post-dose and individual time points. The mean and standarddeviation (SD) of C_(max)/(T_(max)−T_(lag)) for uncoated pellets in themonolithic enteric capsule according to Example 6 was 1714 (SD=847) andfor the commercial capsule product was 1038 (SD=968), which shows that amuch faster absorption rate was achieved in patients treated with themonolithic enteric capsules of Example 6.

The ratio of Example 6 monolithic enteric capsules compared to thecommercial product showed an increase in C_(max) of 56% in in vivotesting, with a ratio of 155.75% (90% confidence interval 86.93, 279.07,geometric least squares means). The ratio of the Example 6 monolithicenteric capsules compared to the commercial product showed an increasein AUC of 132% in in vivo testing, with a ratio of 131.67% (90%confidence upper interval 220.96, geometric least squares means).Despite these increases in bioavailability, the rate of drug eliminationwas similar after release into the gastrointestinal tract, i.e., Example6 vs. commercial product was Kei (1/h) 0.593 (±0.149) vs. 0.60 (±0.203).

The fed samples provided a delayed release beyond the test period. Foodeffect delay is known from the commercial product, which is designatedto be taken at least one hour before meals. The high fat meal did notaffect the integrity of the Example 6 capsules within the stomach.

Table 5 provides the means and standard deviation for thepharmacokinetic parameters for the Example 6 samples, fed and fasted,compared to the commercial product (enteric coated pellets in acapsule).

TABLE 5 Mean ± SD Commercial Ex. 6, Ex. 6 Product PK (fasting) (fed)(fasting) Parameter (Unit) N = 14 N = 14 N = 14 C_(max) (ng/mL) 1382(±545) 256 (±328) 1082 (±511) T_(max) (h)* 2.40 (±1.3) 10.8 (±2.25) 2.14(±1.1) (Median = (Median = (Median = 2.03) 11.63) 2.01) AUC_(0-t) (ng ·h/mL) 2819 (±2003) 264 (±316) 2692 (±2079) AUC_(0-∞) (ng · h/mL) 2876(±2113) 2770 (±2268) K_(el) (1/h) 0.6 (±0.15) 0.6 (±0.20) t_(1/2) (h)1.3 (±00.4) 1.4 (±0.8) (Ln-transformed) Geometric LS Means C_(max)(ng/mL) 1544.72 991.78 AUC_(0-t) (ng · h/mL) 2949.94 2240.46 AUC_(0-∞)(ng · h/mL) 2448.71 2254.23 Ratio (%): Ex. 6 vs Commercial ProductC_(max) (ng/mL) 155.75 AUC_(0-t) (ng · h/mL) 131.67 AUC_(0-∞) (ng ·h/mL) 108.63

Table 6 shows the variability of the pharmacokinetic parameters obtainedaccording to Examples 6 and 7.

TABLE 6 Type of Variability/ Coefficient of Variation PK Parameters (CV%) Intra-subject Esomeprazole AUC_(inf) 40.85 AUC_(t) 83.08 C_(max)97.51 Example 6 Comm. Prod. Inter-subject (Fasting) (Fasting) AUC_(inf)73.43 81.89 AUC_(t) 71.07 77.24 C_(max) 39.45 47.29 T_(max) 53.5 49.5t_(1/2) 33.1 56.21

Example 8

Active ingredients imatinib mesylate, mesalamine, mycophenate sodium,ibuprofen, insulin, desmopressin, and somatropin will be testedaccording to the preceding Examples to illustrate the monolithic entericcapsule systems and methods.

Other embodiments of the present disclosure will be apparent to thoseskilled in the art from consideration of the specification and practiceof the present disclosure. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the present disclosure being indicated by the following claims.

1. An enteric drug delivery system comprising: a monolithic enteric hardcapsule filled with the active pharmaceutical ingredient, wherein theactive pharmaceutical ingredient has not been enterically coated formodified release or gastric protection, wherein less than about 10% ofthe active pharmaceutical ingredient is released from the monolithicenteric capsule after about 2 hours in a pH of about 1.2, wherein atleast about 80% of the active pharmaceutical ingredient is released fromthe monolithic enteric capsule after about 30 min at pH of about 6.8,and wherein more than about 95% of the active ingredient is released inthe intestine; wherein the active pharmaceutical ingredient is a protonpump inhibitor selected from the group consisting of dexlanzoprazole,esomeprazole, ilaprazole, leminoprazole, lanzoprazole, omeprazole,pantoprazole, paripiprazole, rabeprazole, tenatoprazole andcombinations, pharmaceutically acceptable salts, derivatives, andenantiomers thereof.
 2. The system according to claim 1, wherein themonolithic enteric capsule yields a peak plasma concentration (C_(max))that is equal to or higher than the peak plasma concentration achievedby the active pharmaceutical ingredient from administration of an oraldosage form comprising at least one enteric coating for modified releaseor gastric protection, particularly where C_(max) is increased by up toabout 279%.
 3. The system according to claim 1, wherein the monolithicenteric capsule yields an Area Under Curve (AUC_(0-t)) plasmaconcentration of the active pharmaceutical ingredient equal to or higherthan the AUC_(0-t) achieved by the active pharmaceutical ingredient fromadministration of an oral dosage form comprising at least one entericcoating for modified release or gastric protection, particularly whereAUC_(0-t) is increased up to about 220%.
 4. The system according toclaim 1, wherein the monolithic enteric capsule yields an Area UnderCurve (AUC_(0-∞)) plasma concentration of the active pharmaceuticalingredient equal to or higher than the AUC_(0-∞) achieved by the activepharmaceutical ingredient from administration of an oral dosage formcomprising at least one enteric coating for modified release or gastricprotection, particularly where AUC₀₋∞ is increased up to about 162%. 5.The system according to claim 1, wherein the monolithic enteric capsulehas an increase in oral bioavailability from about 10% to about 50% onaverage compared to bioavailability of the active pharmaceuticalingredient in an oral dosage form comprising at least one entericcoating for modified release or gastric protection.
 6. The systemaccording to claim 1, wherein the active pharmaceutical ingredient isesomeprazole or its pharmaceutically acceptable salts.
 7. A method ofincreasing bioavailability of an active pharmaceutical ingredient (API),comprising administering to a human in need thereof a therapeuticallyeffective amount of at least one API in a monolithic enteric hardcapsule, wherein said API has not been coated for modified release orgastric protection, wherein the bioavailability of said API is increasedcompared to API having an enteric coating for modified release orgastric protection.
 8. The method according to claim 7, wherein the APIis acid labile or has gastric side effects. 9-10. (canceled)
 11. Amonolithic enteric capsule, comprising: a non-salified functionalpolymer, said polymer being present in an amount ranging from about 50%to about 75% by weight of the total weight of the empty capsule; atleast one processing aid present in an amount ranging from about 10.5%to about 20% by weight of the total weight of the empty capsule; andwater present in an amount ranging from about 1% to about 20% by weightover the total weight of the empty capsule.
 12. The monolithic entericcapsule according to claim 11, wherein the monolithic enteric capsuleprovides an increased rate of absorption C_(max)/(T_(max)−T_(lag)) forthe active pharmaceutical ingredient after administration to a patientas compared to the rate of absorption of the active pharmaceuticalingredient having an enteric coating for modified release or gastricprotection from about 30 ng/mL/hr to about 3400 ng/mL/hr.
 13. Themonolithic enteric capsule according to claim 11, wherein the monolithicenteric capsule decreases the time to achieve peak plasma concentration(T_(max)−T_(lag)) for the active pharmaceutical ingredient compared tothe active pharmaceutical ingredient coated for modified release orgastric protection in pellets or tablets, preferably decreasing by fromabout 0.1 hour to about 2.0 hours.
 14. The monolithic enteric capsuleaccording to claim 11, wherein the monolithic enteric capsule decreasesthe time to achieve peak plasma concentration for the activepharmaceutical ingredient compared to the active pharmaceuticalingredient coated for modified release or gastric protection in soliddosage forms selected from the group consisting of beads, caplets,capsules, granules, microparticles, multiparticulates, microspheres;powders, pellets, solid lipid pellets, tablets, and combinationsthereof, preferably decreasing by from about 10 minutes to about 90minutes.
 15. The monolithic enteric capsule according to claim 11,wherein the monolithic enteric capsule provides an increased lag timeafter administration to a patient for release of the activepharmaceutical ingredient compared to the active pharmaceuticalingredient coated for modified release or gastric protection in soliddosage forms selected from the group consisting of beads, caplets,capsules, granules, microparticles, multiparticulates, microspheres;powders, pellets, solid lipid pellets, tablets, and combinationsthereof, preferably where the increase in lag time is from about 0.1hour to about 4.3 hours.
 16. The monolithic enteric capsule according toclaim 11, wherein the monolithic enteric capsule lacks internalexcipients.
 17. An oral pharmaceutical dosage form, comprising themonolithic enteric hard capsule of claim 11, wherein the monolithicenteric hard capsule is filled with at least one proton pump inhibitorfree of enteric coating, wherein the monolithic enteric hard capsuleyields a peak plasma concentration higher than the peak plasmaconcentration achieved by the proton pump inhibitor having an entericcoating for modified release or gastric protection.